Drugs are most conventionally administered either orally or by injection. Unfortunately, many medicaments are completely ineffective or of radically reduced efficiency when orally administered since they either are not absorbed or are adversely affected before entering the blood stream and thus do not possess the desired activity. Transdermal delivery when compared to oral delivery avoids the harsh environments of the digestive tract, bypasses gastrointestinal drug metabolism, reduces first-pass effects, and avoids the possible deactivation by digestive and liver enzymes. Conversely, the digestive tract is not subjected to the drug during transdermal administration. On the other hand, the direct injection of the medicament into the bloodstream, while assuring no modification of the medicament in administration, is a difficult, inconvenient, painful and uncomfortable procedure, sometimes resulting in poor patient compliance. This is particularly true for vaccination of children, where the vaccinations must be delivered intramuscularly in a series of injections.
Hence, in principal, transdermal delivery provides for a method of administering drugs that would otherwise need to be delivered via hypodermic injection or intravenous infusion.
The word “transdermal” is used herein to mean the delivery of an agent (e.g., a therapeutic agent such as a drug) into or through the skin for local or systemic therapy. Transdermal agent delivery includes delivery via passive diffusion as well as by other external energy sources including electricity (e.g., iontophoresis) and ultrasound (e.g. phonophoresis). While drugs do diffuse across both the stratum corneum and the epidermis, the rate of diffusion through the intact stratum corneum is often the limiting step. Many compounds require higher delivery rates than can be achieved by simple passive transdermal diffusion. When compared to injections, transdermal agent delivery eliminates the associated pain and reduces the possibility of infection. Theoretically, the transdermal route of agent administration could be advantageous in the delivery of many therapeutic proteins, because proteins are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake. Additionally transdermal devices are more acceptable to patients than injections. However, the transdermal flux of medically useful peptides and proteins is often insufficient to be therapeutically effective due to the large size/molecular weight of these molecules. Often the delivery rate or flux is insufficient to produce the desired effect or the agent is degraded prior to reaching the target sight, for example the patient's blood stream.
Passive transdermal drug delivery systems generally rely on passive diffusion to administer the drug while active transdermal drug delivery systems rely on an external energy source (e.g., electricity) to deliver the drug. Passive transdermal drug delivery systems are more common. Passive transdermal systems have a drug reservoir containing a high concentration of drug adapted to contact the skin where the drug diffuses through the skin and into the body tissues or bloodstream of the patient. The transdermal drug flux is dependent upon the condition of the skin, the size and physical/chemical properties of the drug molecule, and the concentration gradient across the skin. Because of the low skin permeability to many drugs, transdermal delivery has had limited applications. This low permeability is attributed primarily to the stratum corneum, the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. The highly ordered structure of the lipid bilayers confers a relatively impermeable character to the stratum corneum.
One common method of increasing the passive transdermal diffusional drug flux, involves pre-treating the skin with, or co-delivering with the drug, a skin permeation enhancer. A permeation enhancer, when applied to a body surface through which the drug is delivered, enhances the flow of the drug therethrough. However, the efficacy of these methods in enhancing transdermal protein transport has been limited, at least for the larger proteins, due to their size. Active transport systems use an external energy source to assist the drug flux through the stratum corneum. One such enhancement for transdermal drug delivery is referred to as “electrotransport.” This mechanism uses an electrical potential, which results in the application of electric current to aid in the transport of the agent through the body surface, such as skin. Other active transport systems use ultrasound (phonophoresis) or heat as the external energy source.
There also have been many attempts to mechanically penetrate or disrupt the outermost skin layers, thereby creating pathways into the skin in order to enhance the amount of agent being transdermally delivered. Early vaccination devices known as scarifiers generally had a plurality of tines or needles, which are applied to the skin to scratch or make small cuts in the area of application. The vaccine was applied either topically on the skin, such as described in U.S. Pat. No. 5,847,726 issued to Rabenau, or alternatively, as a wetted liquid that may be applied to the tines of the scarifier as shown and described in U.S. Pat. No. 4,453,926, issued to Galy; or U.S. Pat. No. 4,109,655 issued to Charcornac, or U.S. Pat. No. 3,136,314 issued to Kravitz. Scarifiers have been suggested for intradermal vaccine delivery in part because only very small amounts of the vaccine need to be delivered into the skin to be effective in immunizing the patient. Further, the amount of vaccine delivered is not particularly critical since a minimum amount achieves satisfactory immunization as well as an excess amount. However, a serious disadvantage in using a scarifier to deliver a drug is the difficulty in determining the transdermal drug flux and the resulting dosage delivered because it cannot be determined if the minimum amount was delivered. For example, in many instances, the agent disposed upon the skin piercing tines of an intradermal vaccination device is pushed off the tines during skin piercing. Further, many beneficial agents do not have good adhesion characteristics, after being coated onto tines or other skin piercing microprojections, so that the beneficial agent is easily dislodged from the surface of the microprojections. For example, a portion of the beneficial agent may be dislodged from the microprojections during use and not delivered to the patient, resulting in a situation where the patient may not receive the full dosage needed or required. Also, due to the elastic, resilient, and deforming nature of skin that allows it to deflect and resist puncturing, the tiny piercing elements often do not uniformly penetrate the skin and/or are wiped free of a liquid coating of an agent upon skin penetration. Additionally, due to the self healing process of the skin, the punctures or slits made in the skin tended to close up after removal of the piercing elements from the stratum corneum. Thus, the skin acts to remove active agent coating the tiny piercing elements upon penetration. Furthermore, the tiny slits formed by the piercing elements heal quickly after removal of the device, thus, limiting the passage of the agent through the passageways created by the piercing elements and in turn limiting the transdermal flux of such devices.
Other devices that use tiny skin piercing elements to enhance transdermal drug delivery are disclosed in European Patent 0407063A1; U.S. Pat. No. 5,879,326 issued to Godshall et al.; U.S. Pat. No. 3,814,097 issued to Ganderton et al.; U.S. Pat. No. 5,279,544 issued to Gross et al.; U.S. Pat. No. 5,250,023 issued to Lee et al.; U.S. Pat. No. 3,964,482 issued to Gerstel et al.; U.S. Pat. No. Reissue 25,637 issued to Kravitz et al.; and PCT Publications No. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298, and WO 98/29365; all incorporated by reference in their entirety. These devices use piercing elements of various shapes and sizes to pierce the outermost layer (i.e. the stratum corneum) of the skin. The piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet. The piercing elements in some of these devices are extremely small, some having dimensions (i.e., microblade length and width) of only about 25-400 micro-meters and a microblade thickness of only about 5-30 micro-meters. These tiny piercing/cutting elements make correspondingly small microslits in the stratum corneum for enhanced transdermal agent delivery therethrough.
Generally these systems include a reservoir for holding the drug and also a delivery system to transfer the drug from the reservoir through the stratum corneum, such as by hollow tines of the device itself. One example of such a device is disclosed in WO 93/17754, which has a liquid drug reservoir. The reservoir must be pressurized to force the liquid drug through the tiny tubular elements and into the skin. Disadvantages of devices such as these include the added complication and expense of adding a pressurizeable liquid reservoir and complications due to the presence of a pressure-driven delivery system. Another disadvantage of these systems is that they have a limited shelf life due to degradation of the beneficial agent within the liquid reservoir.